Recent experimental and theoretical studies on the dynamics of the reactions of methane with F and Cl atoms have modified our understanding of mode-selective chemical reactivity. The O + methane reaction is also an important candidate to extend our knowledge on the rules of reactivity. Here, we report a unique full-dimensional ab initio potential energy surface for the O(3P) + methane reaction, which opens the door for accurate dynamics calculations using this surface. Quasiclassical trajectory calculations of the angular and vibrational distributions for the ground state and CH stretching excited O + CHD3(v1 = 0,1) → OH + CD3 reactions are in excellent agreement with the experiment. Our theory confirms what was proposed experimentally: The mechanistic origin of the vibrational enhancement is that the CH-stretching excitation enlarges the reactive cone of acceptance.
The HIV-1 envelope (Env) spike, which consists of a compact, heterodimeric trimer of the glycoproteins gp120 and gp41, is the target of neutralizing antibodies. However, the high mutation rate of HIV-1 and plasticity of Env facilitates viral evasion from neutralizing antibodies through various mechanisms. Mutations that are distant from the antibody binding site can lead to escape, probably by changing the conformation or dynamics of Env; however, these changes are difficult to identify and define mechanistically. Here we describe a network analysis-based approach to identify potential allosteric immune evasion mechanisms using three known HIV-1 Env gp120 protein structures from two different clades, B and C. First, correlation and principal component analyses of molecular dynamics (MD) simulations identified a high degree of long-distance coupled motions that exist between functionally distant regions within the intrinsic dynamics of the gp120 core, supporting the presence of long-distance communication in the protein. Then, by integrating MD simulations with network theory, we identified the optimal and suboptimal communication pathways and modules within the gp120 core. The results unveil both strain-dependent and -independent characteristics of the communication pathways in gp120. We show that within the context of three structurally homologous gp120 cores, the optimal pathway for communication is sequence sensitive, i.e. a suboptimal pathway in one strain becomes the optimal pathway in another strain. Yet the identification of conserved elements within these communication pathways, termed inter-modular hotspots, could present a new opportunity for immunogen design, as this could be an additional mechanism that HIV-1 uses to shield vulnerable antibody targets in Env that induce neutralizing antibody breadth.
Neuromusculoskeletal models solve the basic problem of determining how the body moves under the influence of external and internal forces. Existing biomechanical modeling programs often emphasize dynamics with the goal of finding a feed-forward neural program to replicate experimental data or of estimating force contributions or individual muscles. The computation of rigid-body dynamics, muscle forces, and activation of the muscles are often performed separately. We have developed an intrinsically forward computational platform (Neuromechanic, www.neuromechanic.com) that explicitly represents the interdependencies among rigid body dynamics, frictional contact, muscle mechanics, and neural control modules. This formulation has significant advantages for optimization and forward simulation, particularly with application to neural controllers with feedback or regulatory features. Explicit inclusion of all state dependencies allows calculation of system derivatives with respect to kinematic states and muscle and neural control states, thus affording a wealth of analytical tools, including linearization, stability analyses and calculation of initial conditions for forward simulations. In this review, we describe our algorithm for generating state equations and explain how they may be used in integration, linearization, and stability analysis tools to provide structural insights into the neural control of movement.
Phage therapy is the use of bacterial viruses (phages) to treat bacterial infections, a medical intervention long abandoned in the West but now experiencing a revival. Currently, therapeutic phages are often chosen based on limited criteria, sometimes merely an ability to plate on the pathogenic bacterium. Better treatment might result from an informed choice of phages. Here we consider whether phages used to treat the bacterial infection in a patient may specifically evolve to improve treatment on that patient or benefit subsequent patients. With mathematical and computational models, we explore in vivo evolution for four phage properties expected to influence therapeutic success: Generalized phage growth, phage decay rate, excreted enzymes to degrade protective bacterial layers, and growth on resistant bacteria. Within-host phage evolution is strongly aligned with treatment success for phage decay rate but only partially aligned for phage growth rate and growth on resistant bacteria. Excreted enzymes are mostly not selected for treatment success. Even when evolution and treatment success are aligned, evolution may not be rapid enough to keep pace with bacterial evolution for maximum benefit. An informed use of phages is invariably superior to naive reliance on within-host evolution.
In mathematical epidemiology, a well-known formula describes the impact of heterogeneity on the basic reproductive number, R0, for situations in which transmission is separable and for which there is one source of variation in susceptibility and one source of variation in infectiousness. This formula is written in terms of the magnitudes of the heterogeneities, as quantified by their coefficients of variation, and the correlation between them. A natural question to ask is whether analogous results apply when there are multiple sources of variation in susceptibility and/or infectiousness. In this paper we demonstrate that with three or more coupled heterogeneities, R0 under separable transmission depends on details of the distribution of the heterogeneities in a way that is not seen in the well-known simpler situation. We provide explicit formulae for the cases of multivariate normal and multivariate log-normal distributions, showing that R0 can again be expressed in terms of the magnitudes of the heterogeneities and the pairwise correlations between them. The formulae, however, differ between the two multivariate distributions, demonstrating that no formula of this type applies generally when there are three or more coupled heterogeneities. We see that the results of the formulae are approximately equal when heterogeneities are relatively small and show that an earlier result in the literature (Koella, 1991) should be viewed in this light. We provide numerical illustrations of our results and discuss a setting in which coupled heterogeneities are likely to have a major impact on the value of R0. We also describe a rather surprising result: in a system with three heterogeneities, R0 can exhibit non-monotonic behavior with increasing levels of heterogeneity, in marked contrast to the familiar two heterogeneity setting in which R0 either increases or decreases with increasing heterogeneity.
Purpose: Pediatric and adult patients with sickle cell anemia (SCA) are at increased risk of stroke and cerebrovascular accident. In the general adult population, there is a relationship between arterial hemodynamics and pathology; however, this relationship in SCA patients remains to be elucidated. The aim of this work was to characterize circle of Willis hemodynamics in patients with SCA and quantify the impact of viscosity choice on pathophysiologically-relevant hemodynamics measures. Methods: Based on measured vascular geometries, time-varying flow rates, and blood parameters, detailed patient-specific simulations of the circle of Willis were conducted for SCA patients (n = 6). Simulations quantified the impact of patient-specific and standard blood viscosities on wall shear stress (WSS). Results: These results demonstrated that use of a standard blood viscosity introduces large errors into the estimation of pathophysiologically-relevant hemodynamic parameters. Standard viscosity models overpredicted peak WSS by 55% and 49% for steady and pulsatile flow, respectively. Moreover, these results demonstrated non-uniform, spatial patterns of positive and negative WSS errors related to viscosity, and standard viscosity simulations overpredicted the time-averaged WSS by 32% (standard deviation = 7.1%). Finally, differences in shear rate demonstrated that the viscosity choice alters the simulated near-wall flow field, impacting hemodynamics measures. Conclusions: This work presents simulations of circle of Willis arterial flow in SCA patients and demonstrates the importance and feasibility of using a patient-specific viscosity in these simulations. Accurately characterizing cerebrovascular hemodynamics in SCA populations has potential for elucidating the pathophysiology of large-vessel occlusion, aneurysms, and tissue damage in these patients.
We investigated whether local hemodynamics were associated with sites of plaque erosion and hypothesized that patients with plaque erosion have locally elevated WSS magnitude in regions where erosion has occurred. We generated 3D, patient-specific models of coronary arteries from biplane angiographic images in 3 human patients with plaque erosion diagnosed by optical coherence tomography. Using computational fluid dynamics, we simulated pulsatile blood flow and calculated both wall shear stress (WSS) and oscillatory shear index (OSI). We also investigated anatomic features of plaque erosion sites by examining branching and local curvature in X-ray angiograms of barium-perfused autopsy hearts. Neither high nor low magnitudes of mean WSS were associated with sites of plaque erosion. OSI and local curvature were also not associated with erosion. Anatomically, 8 of 13 hearts had a nearby bifurcation upstream of the site of plaque erosion. This study provides preliminary evidence that neither hemodynamics nor anatomy are predictors of plaque erosion, based upon a very unique dataset. Our sample sizes are small, but this dataset suggests that high magnitudes of WSS, one potential mechanism for inducing plaque erosion, are not necessary for erosion to occur.
by
Sarah T. Plummer;
Christoph P. Hornik;
Hamilton Baker;
Gregory A. Fleming;
Susan Foerster;
Matthew Ferguson;
Andrew C. Glatz;
Russel Hirsch;
Jeffrey P. Jacobs;
Kyong-Jin Lee;
Alan B. Lewis;
Jennifer S. Li;
Mary Martin;
Diego Porras;
Wolfgang A. K. Radtke;
John F. Rhodes;
Julie A. Vincent;
Jeffrey D. Zampi;
Kevin D. Hill
Objectives: Aortic arch reconstruction in children with single ventricle lesions may predispose to circulatory inefficiency and maladaptive physiology leading to increased myocardial workload. We sought to describe neoaortic anatomy and physiology, risk factors for abnormalities, and impact on right ventricular function in patients with single right ventricle lesions after arch reconstruction. Methods: Prestage II aortic angiograms from the Pediatric Heart Network Single Ventricle Reconstruction trial were analyzed to define arch geometry (Romanesque [normal], crenel [elongated] , or gothic [angular]), indexed neoaortic dimensions, and distensibility. Comparisons were made with 50 single-ventricle controls without prior arch reconstruction. Factors associated with ascending neoaortic dilation, reduced distensibility, and decreased ventricular function on the 14-month echocardiogram were evaluated using univariate and multivariable logistic regression. Results: Interpretable angiograms were available for 326 of 389 subjects (84%). Compared with controls, study subjects more often demonstrated abnormal arch geometry (67% vs 22%, P < .01) and had increased ascending neoaortic dilation (Z score 3.8 ± 2.2 vs 2.6 ± 2.0, P < .01) and reduced distensibility index (2.2 ± 1.9 vs 8.0 ± 3.8, P < .01). Adjusted odds of neoaortic dilation were increased in subjects with gothic arch geometry (odds ratio [OR], 3.2 vs crenel geometry, P < .01) and a right ventricle-pulmonary artery shunt (OR, 3.4 vs Blalock–Taussig shunt, P < .01) but were decreased in subjects with aortic atresia (OR, 0.7 vs stenosis, P < .01) and those with recoarctation (OR, 0.3 vs no recoarctation, P = .04). No demographic, anatomic, or surgical factors predicted reduced distensibility. Neither dilation nor distensibility predicted reduced right ventricular function. Conclusions: After Norwood surgery, the reconstructed neoaorta demonstrates abnormal anatomy and physiology. Further study is needed to evaluate the longer-term impact of these features.
Virtual organisms animated by a selectionist theory of behavior dynamics worked on concurrent random interval schedules where both the rate and magnitude of reinforcement were varied. The selectionist theory consists of a set of simple rules of selection, recombination, and mutation that act on a population of potential behaviors by means of a genetic algorithm. An extension of the power function matching equation, which expresses behavior allocation as a joint function of exponentiated reinforcement rate and reinforcer magnitude ratios, was fitted to the virtual organisms' data, and over a range of moderate mutation rates was found to provide an excellent description of their behavior without residual trends. The mean exponents in this range of mutation rates were 0.83 for the reinforcement rate ratio and 0.68 for the reinforcer magnitude ratio, which are values that are comparable to those obtained in experiments with live organisms. These findings add to the evidence supporting the selectionist theory, which asserts that the world of behavior we observe and measure is created by evolutionary dynamics.
Background: Three-dimensional design simulations of coronary metallic stents utilizing mathematical
and computational algorithms have emerged as important tools for understanding biomechanical
stent properties, predicting the interaction of the implanted platform with the adjacent tissue, and
informing stent design enhancements. Herein, we demonstrate the hemodynamic implications
following virtual implantation of bioresorbable scaffolds using finite element methods and advanced
computational fluid dynamics (CFD) simulations to visualize the device-flow interaction immediately
after implantation and following scaffold resorption over time.
Methods and Results: CFD simulations with time averaged wall shear stress (WSS) quantification
following virtual bioresorbable scaffold deployment in idealized straight and curved geometries were
performed. WSS was calculated at the inflow, endoluminal surface (top surface of the strut), and
outflow of each strut surface post-procedure (stage I) and at a time point when 33% of scaffold
resorption has occurred (stage II). The average WSS at stage I over the inflow and outflow surfaces was
3.2 and 3.1 dynes/cm2 respectively and 87.5 dynes/cm2 over endoluminal strut surface in the straight
vessel. From stage I to stage II, WSS increased by 100% and 142% over the inflow and outflow surfaces,
respectively, and decreased by 27% over the endoluminal strut surface. In a curved vessel, WSS change
became more evident in the inner curvature with an increase of 63% over the inflow and 66% over the
outflow strut surfaces. Similar analysis at the proximal and distal edges demonstrated a large increase
of 486% at the lateral outflow surface of the proximal scaffold edge.
Conclusions: The implementation of CFD simulations over virtually deployed bioresorbable
scaffolds demonstrates the transient nature of device/flow interactions as the bioresorption process
progresses over time. Such hemodynamic device modeling is expected to guide future bioresorbable
scaffold design.